Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) was identified as a humoral factor that promotes proliferation of bone marrow granulocyte and macrophage progenitor cells and promotes formation of granulocyte and macrophage colonies in vitro.
GM-CSF is now known to be a stimulating factor for a wide range of cell types. It induces differentiation and proliferation of granulocyte-macrophage lineage blood cells, augments functions of antigen-presenting cells, maintains functions of some kinds of epithelial cells and induces functions of alveolar macrophages (e.g., enhances surfactant catabolism, bactericidal function, and Fc receptor expression). The Cytokine Handbook, 4th edition, Thomson, A. et al. (eds.), Academic Press, 2003.
GM-CSF is known to cause various diseases, including 1) allergic diseases such as asthma, atopy, and pollinosis, 2) graft rejection, and graft-versus-host disease (GVHD), and 3) autoimmune diseases, such as rheumatoid arthritis.
For example, human GM-CSF (hGM-CSF) is over-expressed in the lungs of allergic subjects and in the joints of rheumatoid arthritis patients; hGM-CSF mRNA is over-expressed in skin of allergic subjects. It has also been reported that the survival of monocytes, which are inflammation-inducing cells in atopic dermatitis, is enhanced by GM-CSF production. Bratton, D. L. et al., Granulocyte macrophage colony-stimulating factor contributes to enhanced monocyte survival in chronic atopic dermatitis. J. Clin. Invest., 95: 211-218, 1995.
In addition, it has been shown that GM-CSF stimulates proliferation of leukemic cells. Therefore, GM-CSF is considered to be a factor that causes leukemia.
It would be useful to have approaches to treating diseases and conditions caused by human GM-CSF. One approach to therapy for such diseases and conditions is to bind hGM-CSF and inhibit its biological activity. This might be done, for example, by administering anti-hGM-CSF monoclonal antibodies that have high affinity and sufficient neutralizing activity against hGM-CSF but do not induce immunological reaction.
However, hGM-CSF-inhibiting antibodies reported to date do not have sufficient neutralizing activity against hGM-CSF. Further, it seems very likely that presently-available anti-hGM-CSF monoclonal antibodies will induce an unwanted immune response in recipients. Polyclonal antibody and monoclonal antibody are generally derived from experimental animals, such as mice, rabbits and caprines. However, the obtained antibodies have a sequence characteristic of the kind of animals used for their production. If they are administered to humans, the human immune system might recognize the antibodies as foreign, and then, human anti-animal antibody response (that is, antibody produces its own antibody) may be caused.
In addition, long-term administration is necessary for treatment of such diseases and problems might arise as a result, such as safety problems that might be caused by small amounts of impurities in medicines administered. Antibodies with greater neutralizing activity than those presently available would be valuable as therapeutics from the view point of effectiveness, safety, and medical expense.